Renin is a proteolytic enzyme having a molecular weight of about 40,000, produced and secreted by juxtaglomerular cells in the kidney. This acts on the plasma renin substrate, angiotensinogen, to yield decapeptide angiotension I which is converted into angiotensin II by angiotensin I converting enzyme.
It is well known that angiotensin II contracts the vascular smooth muscle and acts on the adrenal cortex to screte the aldosterone which regulates salt and water balance. Accordingly, the renin-angiotensin system plays an important role in hypertension. In fact, a specific inhibitor of angiotensin I converting enzyme has been investigated and developed as a practical medicament for hypertension. Thus, an effective inhibitor of renin has long been sought as an agent for treatment of hypertension, especially renin-associated hypertension. As a result, it has been found that certain peptides shown renin inhibitory effect, as described in Biochemical and Biophysical Research Communications, Vol. 118, pages 929-933, 1984; Japanese Patent Publication No. 39149/83, Japanese Patent Applications (OPI) Nos. 110661/84 and 155345/84 (The term "OPI" as used herein refers to a Japanese unexamined published patent application); and European Patent Applicatins 77029(A.sub.2), 77028(A.sub.2) and 81783(A.sub.2).
The noted Biochemical and Biophysical Research Communications article discloses a dipeptide represented by the formula ##STR2## His represents an L-histidyl group, and C* represents an L-configurational carbon atom. However, this peptide shows a weak renin inhibitory activity, and thus was hardly useful as a practical medicament.
Japanese Patent Publication No. 39149/83 above discloses peptides represented by the formula ##STR3## wherein R.sub.12 represents a methyl group, an ethyl group, a benzyl group, an adamantyl group or a benzyloxy group, Q represents an L-phenylalanyl group, an L-prolyl-L-phenylalanyl group or an L-histidyl-L-prolyl-L-phenylalanyl group, His represents an L-histidyl group, R.sub.13 represents an isopropyl group, and C* represents an L-configurational carbon atom. These peptides show a renin inhibitory effect, however, they are easily digested by proteolytic enzymes of the gastrointestinal tract such as chymotrypsins. Therefore, they have a drawback that their renin inhibitory effect can not be expected when they are administered orally.
On the other hand, the peptides disclosed in the above European Patent Applications are polypeptides and have difficulties in their preparation and purification. Furthermore, they lose their pharmacological effects when administered orally similar to the peptides disclosed in the Japanese Patent Publication No. 39149/83, and the extent to which they are useful is thus limited.
Thus, development of renin inhibitors which can display a sufficient therapeutic effect by oral administration has long been desired.